The recognized incidence and pathological impact of traumatic brain injury (TBI) has increased tremendously in recent year. In particular the causal links between TBI and chronic traumatic encephalopathy (CTE) are becoming better understood. Many of the pathological hallmarks of Alzheimer's disease (AD) are shared with early changes in TBI and with the pathology of CTE. Of note are the rapid elevations of the amyloid-beta (A?) peptide after TBI and the accumulation of A? in relation to CTE. Considering the importance of A? to AD, it is reasonable to implicate this peptide in the response to TBI and the development of CTE. Natural mechanisms of clearance of A? are important in the progression of AD and so these clearance mechanisms may also be important in TBI/CTE. Of note are the A?-degrading enzymes neprilysin (NEP) and its homolog neprilysin-2 (NEP2) which are important for controlling cerebral A? levels. Therefore, we propose a role for these enzymes in TBI/CTE. The central hypothesis is that NEP or NEP2 expression is important for effective recovery after TBI and protects from the development of CTE. In Aim 1, we will test this hypothesis through the use of NEP and NEP2 knockout as well as NEP transgenic mice which will receive mild-repetitive or single severe TBI, after which they will be assessed for neurological function and pathology acutely after injury. We predict that the lack of NEP or NEP2 will exacerbate aspects of acute pathology after injury while NEP overproduction will ameliorate pathology. In Aim 2 we will test for the effects of NEP or NEP2 alterations on chronic development of CTE-like pathology months after injury involving multiple mild or single severe TBI. In this aim we expect that decreased NEP or NEP2 will exacerbate, while increased NEP will protect against aspects of CTE-like pathology (learning and memory deficits, anxiety) in our models. This work is innovative because the effects of reduced or enhanced NEP-like expression on the progression of TBI and CTE have not been addressed. Also, the role of the NEP/NEP2 substrate, A?, in TBI and CTE is also not yet fully understood, and this project will investigate an alternate means of manipulating A? levels without altering APP and BACE1 or using secretase inhibitors. These experiments will shed light on the role of these A?-degrading endopeptidases in TBI and CTE allowing for the potential development of therapies based on augmenting their activity post injury. Furthermore, this work could help in identifying gene expression markers that predict outcome after TBI.